The approach of Oncogene Science for the treatment of sickle cell anemia is to identify chemical compounds which elevate transcription of the human fetal globin gene and thereby prevent sickle cell anemia or beta- thalassemia. Sickle cell disease is an often crippling disease afflicting 1 in 400 Afro-Americans. The disease results from a glutamic acid to valine change at position 6 of the adult beta-globin gene (Hb to HbS) resulting in an irreversible deformation of red blood cells, hemolytic anemia, splenic atrophy and blood vessel occlusion. P-thalassemia is a common lethal disease in the Mediterranean basin and in Southeast Asia which results from abrogation of beta-globin gene expression. Genetic evidence suggests a 30-40% induction in gamma-globin gene expression should effectively treat sickle cell patients and obviate the need for transfusion of beta-thalassemia patients. In Phase I, we propose to engineer erythroid cell lines containing stably integrated DNA constructs which measure changes in gamma-globin gene expression in response to drug treatment. These lines will form the basis for both drug screening and for mechanistic follow-up of lead compounds. Using a novel robotic drug screen capable of screening 3,000 compounds per week against multiple target genes, we propose to screen for chemical compounds which elevate transcription of the human gamma-globin gene and thereby prevent sickle cell anemia or beta-thalassemia.